DESCRIPTION (provided by applicant Loss of the quiescent endothelial phenotype is central to the pathogenesis and progression of a broad spectrum of severe diseases including diabetic complications, sepsis and cardiovascular disease. The current dearth of therapies available to treat vascular dysfunction in these diseases underscores the need to develop new approaches for treatment. We suggest that the Angiopoietin-Tie2/Tek vascular signaling pathway is a promising new target. For example, delivery of Angiopoietin1, prevents vascular leak and inflammation, while promoting endothelial survival in both cell culture and transgenic models. In patients with critical vascular diseases, alterations in circulating Angiopoietin (Angpt) levels ar closely linked to increased morbidity and mortality. Accordingly, we hypothesized that activation of the Tie2 receptor would restore vascular quiescence and function in disease states such as diabetic nephropathy. To test this hypothesis and test the capacity of potent on-target therapies, we will combine studies using robust, genetic animal models, small molecule inhibitors and proteomic strategies for defining the role of the Angiopoietin-Tie2/Tek pathway in vascular diseases. Using these approaches, we will precisely characterize, for the first time, the function(s) and contributions of each of the major Angpt ligands in activation of the Tie2 receptor in the vasculature in vivo, and determine whether inhibition of the phosphatase, VE-PTP, can activate Tie2 in vivo and protect the endothelium from injury in a disease such as diabetes. We will also characterize the complete phosphoproteome of Tie2 and the related ligandless-receptor Tie1, to designate specified vascular functions and effectors for each individual phosphorylation site, ultimately paving the way to improved drug design for vascular dysfunction. Despite the current intense interest in the Angpt-Tie2 pathway by clinicians and pharma, large gaps exist in our knowledge surrounding fundamental aspects of its function(s) at the whole animal, tissue and molecular level. Our studies will provide critical new insights, which are necessary for providing the rationale for supporting clinical applications of this promising therapeutic target.